Most of the approximately 20 million Americans afflicted with sleep related breathing disorders (SRBD) develop cognitive deficits in areas such as alertness, sustained attention, working and long-term episodic memory, ability to learn new information and mental flexibility. Despite decades of research, clinical investigations have not clarified the mechanisms by which SRBD produce cognitive impairment. These cognitive impairments can be particularly debilitating following acute apnea exacerbation. This is an important problem as individuals with chronic SRBD often experience acute exacerbations inter-current to use of alcohol, sedative or hypnotic use, infections, allergies or poor adherence to positive airway pressure therapy. Very little is understood about how acute apnea exacerbation affects brain systems critical for cognition. Recent findings from our laboratory showed in Brown-Norway rats, which exhibit a moderate level of spontaneous sleep apneas, that acute apnea exacerbation produced both reversal learning and working memory deficits. Moreover, there is accumulating evidence that cholinergic signaling in the pedunculopontine tegmental nucleus (PPT), septohippocampal complex and dorsomedial striatum support working memory and cognitive flexibility. A central hypothesis of this research proposal is that acute exacerbatio of spontaneous sleep-related apnea perturbs brain cholinergic signaling, contributing to impaired cognitive functioning. Better understanding of how apnea exacerbation affects brain cholinergic signaling may provide new insights into SRBD pathophysiology and development of effective treatments to alleviate cognitive deficits attendant to acute apnea exacerbation. The proposed project will systematically investigate how acute apnea exacerbation affects brain cholinergic signaling at a cellular, extracellular and receptor level in multiple brain regions tha relates to working memory and cognitive flexibility deficits. This will be conducted in both male and female rats. Aim 1 will define the effect of apnea exacerbation on bursting of PPT cholinergic neurons. Aim 2 will test the hypothesis that acute exacerbation of SRBD alters ACh output in PPT, septohippocampal complex and dorsomedial striatum during sleep, wake and/or cognitive performance. Aim 3 will test the hypothesis that manipulation of muscarinic cholinergic receptor activity in the PPT, septohippocampal complex and/or dorsomedial striatum before acute apnea exacerbation or prior to behavioral testing can alleviate deficits in working memory and reversal learning. Our overall aim is to foster the development of important new knowledge regarding the neurochemical mechanisms underlying cognitive deficits induced by acute apnea exacerbation that can translate into better and individualized treatment approaches.